Currently, the gold standard for evaluating skeletal health and predicting fracture risk in human studies of osteoporosis and other metabolic bone diseases is measurement of areal bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA). However, there are major scientific and technical limitations to DXA. From a scientific perspective, DXA provides only areal BMD measurements and does not provide information about bone architecture such as trabecular number, trabecular thickness, trabecular connectivity, or cortical thickness. These parameters, which contribute to bone quality, are likely responsible, at least in part, for the observations that many fractures occur among patients with normal BMD, that small changes in areal BMD with antiresorptive therapy result in greater than expected reductions in fracture risk, and that changes in BMD following antiresorptive therapy explain a small proportion of the variance in fracture risk reduction. From a technical perspective, DXA does not measure true density, can be markedly altered by degenerative disease in the spine (particularly in men and elderly subjects), is strongly affected by the amount and distribution of surrounding soft tissue, and cannot separate cortical from trabecular bone. Currently, the gold standard for assessing cortical and trabecular microarchitecture is iliac crest biopsy. This procedure is quite invasive so that few subjects are willing to undergo it once, let alone repeatedly in long-term studies. Moreover, reproducibility of bone histomorphometry is poor further limiting its utility in longitudinal bone studies. XtremeCT is a new technique that produces high resolution images of bone that allow a non- invasive assessment of cortical and trabecular microstructure. In essence, XtremeCT is a virtual bone biopsy that can be performed with limited x-ray exposure and is highly reproducible. Thus, it is an ideal technique to use in studies of metabolic bone disease as a complement to DXA to provide critical information about changes in bone architecture and to circumvent limitations of DXA in many key populations. Currently, there are only 3 XtremeCT machines in the US and none in New England. With advances in technology, it appears likely that XtremeCT will be an indispensable tool for state-of-the-art clinical research in metabolic bone disease. We propose to use XtremeCT in a wide range of studies of bone disease that span a multitude of disciplines and serve a wide range of investigators in Boston and throughout New England. [unreadable] [unreadable] [unreadable]